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  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
  • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
  • C12N9/2462—Lysozyme (3.2.1.17)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
  • A61K38/4813—Exopeptidases (3.4.11. to 3.4.19)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
  • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
  • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
  • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
  • C12Y302/01017—Lysozyme (3.2.1.17)

Definitions

• the present invention relates to the field of medicine, specifically to the field of treatment of a malignant condition associated with infection with a bacterium that aggravates and/or induces proliferation of the malignant conditions.
• Oncogenic bacteria can be a major problem in cancer patients.
• bacteria play a role in pathogenesis and/or oncogenesis.
• Helicobacter pylori infection is e.g. closely related with chronic gastritis, gastric duodenal ulcer, and mucosa associated diseases such as lymphoma and gastric cancer (Nervi G, et al. 2006, Does Helicobacter pylori infection eradication modify peptic ulcer prevalence? A 10 years' endoscopical survey. World J Gastroenterol 12: 2398-2401 ; Kamangar et al. 2007, Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China. Br J Cancer 96: 172-176).
• SEA Staphylococcal enterotoxin A
• CTCL cutaneous T-cell lymphoma
• SEA Staphylococcal enterotoxin A
• antibiotics have the disadvantage that there is factual chance that the target bacteria become resistant (e.g. MRSA).
• MRSA multi-resistant virus
• antibiotics are not very specific and will disturb the balance of commensal benign bacteria; said balance is already fragile and compromised in cancer patients.
• Figure 1A Proliferation of a malignant and a non-malignant (Mycosis Fungoides) patient derived CTCL cell line with and without alpha-toxin from Staphylococcus aureus.
• Figure 1 B Cytotoxicity assay of MART-1 specific CD8 T cells directed against peptide pulsed Mad cells with and without alpha-toxin from Staphylococcus aureus. Description of the invention
• an endolysin can effectively be used in the treatment of cancer. Without being bound by theory, it is believed that the specificity of the bacteriophage endolysin in killing target bacteria together with its effectiveness in killing target bacteria provides the unexpected superior beneficial effect in the treatment of cancer.
• the invention provides for an endolysin specific for an oncogenic bacterium for use in the prevention, delay or treatment of cancer in a subject in need thereof.
• an oncogenic bacterium is an oncogenic bacterium according to general knowledge in the field, but also a bacterium that in a malignancy associated with infection with said bacterium, aggravates and/or induces proliferation of the malignant condition.
• the oncogenic bacterium may be any oncogenic bacterium. It may be a bacterium selected from the group consisting of Staphylococcus, Streptococcus (such as S. pyogenes, S. agalactiae and S. pneumonia), Actinomyces, Nocardia, Bacillus (such as B. anthracis), Coxiella (such as Coxiella burnetii), Rickettsia, Mycobacteria (such as M. tuberculosis and M. leprae), Legionella (such as L. pneumophila), Mycoplasma, Salmonella (such as S. typhimurium), Shigella (such as S.
• Staphylococcus such as S. pyogenes, S. agalactiae and S. pneumonia
• Actinomyces Nocardia
• Bacillus such as B. anthracis
• Coxiella such as Coxiella burnetii
• dysenteriae Yersinia (such as Y. pestis), Brucella, Listeria (such as L. monocytogenesis), Actinobacillus (such as A. actinomycetemcomitans), Gardnerella (such as G. vaginalis), Chlamydia (such as C. trachomatis), and Chlamidophila; a more preferred bacterium is a species of Staphylococcus; a preferred species of Staphylococcus is S. aureus.
• a preferred S. aureus is an antibiotic resistant Staphylococcus aureus, such as a methicillin resistant Staphylococcus aureus (MRSA).
• the endolysin according to the invention is a Staphylococcus-specific endolysin, meaning that it will lyse Staphylococcus efficiently but does not substantially lyse other bacteria than Staphylococcus.
• CBD C-terminal cell wall-binding domain
• CHAP histidine-dependent amidohydrolases/peptidase
• Ply2638 of an N-terminal glycyl-glycine endopeptidase domain with Peptidase_M23 homology, the latter three domains exhibiting peptidoglycan hydrolase activity each with distinct target bond specificity and generally named as enzymatically active domains.
• the Ply2638 endolysin is set forward in SEQ ID NO: 1 and SEQ ID NO: 2 (see Table 1 ); several endolysin domains are set forward in SEQ ID NO: 3 to SEQ ID NO: 18 (see Table 1 ), these domains are preferred domains according to the invention.
• a more preferred endolysin according to the invention is a recombinant endolysin, more preferably a recombinant Staphylococcus-specific endolysin, even more preferably a recombinant Staphylococcus-specific chimeric endolysin comprising one or more heterologous domains.
• endolysins are comprised of different subunits (domains); e.g.
• CBD cell wall-binding domain
• enzymatic domains having peptidoglycan activity such as an amidase domain, an M23 peptidase domain and a CHAP (cysteine, histidine-dependent amidohydrolases/peptidases) domain.
• An example of a Staphylococcus-specific chimeric endolysin comprising one or more heterologous domains is an endolysin comprising an Amidase domain of bacteriophage Ply2638, an M23 peptidase domain of lysostaphin (S. simulans) and a cell wall- binding domain of bacteriophage Ply2638.
• Staphylococcus-specific chimeric endolysin is a preferred endolysin according to the invention and is extensively described in WO2012/150858, which is herein incorporated by reference in its entirety.
• Other preferred endolysins according to the invention are extensively described in WO2013/169104, which is herein incorporated by reference in its entirety.
• Other preferred endolysins according to the invention are extensively described in WO2017/046021 , which is herein incorporated by reference in its entirety.
• the present invention may conveniently be combined with the embodiments and endolysins of WO2016/142445, which is herein incorporated by reference in its entirety.
• intracellular Staphylococcus aureus infections are combatted using an agent the increases the intracellular pH combined with an endolysin that is capable of entry into the cell.
• endolysins that are capable of entering the cell are preferred endolysins according to the invention.
• a further preferred endolysin according to the invention is one selected from the group consisting of the endolysins depicted as SEQ ID NO: 19 to SEQ ID NO: 75 in Table 1.
• an endolysin domain according to the invention has at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more preferably 100% sequence identity with a domain depicted in WO2012/150858, WO2013/169104, WO2016/142445 or in any of SEQ ID NO: 3 to SEQ ID NO: 18 (see Table 1 ).
• an endolysin according to the invention has at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more preferably 100% sequence identity with an endolysin depicted in WO2012/150858, WO2013/169104, WO2016/142445 or in any of SEQ ID NO: 1 , 2 and SEQ ID NO: 19 to SEQ ID NO: 75 (see Table 1 ) ⁇
• the person skilled in the art will comprehend that mixes of different endolysins may be used in the present invention, e.g. a mix comprising two, three or four endolysins according to the invention.
• the subject is a vertebrate, preferably a mammal, more preferably a human.
• the type of cancer to be treated by be any type of cancer where oncogenic bacteria are associated with the pathogenesis and oncogenesis of the cancer.
• a preferred cancer is a mucosa associated cancer such as (skin)lymphoma and gastric cancer.
• a more preferred cancer is cutaneous T-cell lymphoma (CTCL).
• CTCL cutaneous T-cell lymphoma
• the person skilled in the art will comprehend that treatment with the endolysin according to the invention may conveniently be combined with other drugs, such as other anti-cancer medicaments.
• the compounds be present in individual compositions or may be present in a single composition.
• an endolysin according to the invention may be present in a composition further comprising an excipient, preferably a pharmaceutically acceptable excipient.
• a further anticancer medicament may be present, such as a chemotherapeutic agent and a monoclonal antibody.
• the medical treatment according to the invention includes an endolysin specific for an oncogenic bacterium for the manufacture of a medicament for the prevention, delay or treatment of cancer in a subject in need thereof as well as a method for the prevention, delay or treatment of cancer in a subject in need thereof, comprising administration of an endolysin specific for an oncogenic bacterium to the subject.
• the embodiments are preferably those as defined here above.
• Uneven SEQ ID NOs: 1 - 71 represent the coding sequences (CDS) of even SEQ ID NOs: 2 - 72 that represent the respective polypeptide (PRT) sequences.
• sequence identity is herein defined as a relationship between two or more amino acid (peptide, polypeptide, or protein) sequences or two or more nucleic acid (nucleotide, polynucleotide) sequences, as determined by comparing the sequences.
• identity also means the degree of sequence relatedness between amino acid or nucleotide sequences, as the case may be, as determined by the match between strings of such sequences.
• similarity between two amino acid sequences is determined by comparing the amino acid sequence and its conserved amino acid substitutes of one peptide or polypeptide to the sequence of a second peptide or polypeptide.
• identity or similarity is calculated over the whole SEQ ID NO as identified herein.
• Identity and similarity can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heine, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991 ; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48: 1073 (1988).
• Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Preferred computer program methods to determine identity and similarity between two sequences include e.g. the GCG program package (Devereux, J., et al., Nucleic Acids Research 12 (1 ): 387 (1984)), BestFit, BLASTP, BLASTN, and FASTA (Altschul, S. F. et al., J. Mol. Biol. 215:403-410 (1990).
• the BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, MD 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990).
• the well-known Smith Waterman algorithm may also be used to determine identity.
• Preferred parameters for polypeptide sequence comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970); Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA. 89: 10915-10919 (1992); Gap Penalty: 12; and Gap Length Penalty: 4.
• a program useful with these parameters is publicly available as the "Ogap" program from Genetics Computer Group, located in Madison, Wl. The aforementioned parameters are the default parameters for amino acid comparisons (along with no penalty for end gaps).
• Preferred parameters for nucleic acid comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol.
• a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulphur-containing side chains is cysteine and methionine.
• Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine- tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine.
• Substitutional variants of the amino acid sequence disclosed herein are those in which at least one residue in the disclosed sequences has been removed and a different residue inserted in its place.
• the amino acid change is conservative.
• Preferred conservative substitutions for each of the naturally occurring amino acids are as follows: Ala to ser; Arg to lys; Asn to gin or his; Asp to glu; Cys to ser or ala; Gin to asn; Glu to asp; Gly to pro; His to asn or gin; lie to leu or val; Leu to ile or val; Lys to arg; gin or glu; Met to leu or ile; Phe to met, leu or tyr; Ser to thr; Thr to ser; Trp to tyr; Tyr to trp or phe; and, Val to ile or leu.
• nucleic acid molecule or “polynucleotide” (the terms are used interchangeably herein) is represented by a nucleotide sequence.
• a “polypeptide” is represented by an amino acid sequence.
• a “nucleic acid construct” is defined as a nucleic acid molecule which is isolated from a naturally occurring gene or which has been modified to contain segments of nucleic acids which are combined or juxtaposed in a manner which would not otherwise exist in nature.
• a nucleic acid molecule is represented by a nucleotide sequence.
• a nucleotide sequence present in a nucleic acid construct is operably linked to one or more control sequences, which direct the production or expression of said peptide or polypeptide in a cell or in a subject.
• “Operably linked” is defined herein as a configuration in which a control sequence is appropriately placed at a position relative to the nucleotide sequence coding for the polypeptide of the invention such that the control sequence directs the production/expression of the peptide or polypeptide of the invention in a cell and/or in a subject. "Operably linked” may also be used for defining a configuration in which a sequence is appropriately placed at a position relative to another sequence coding for a functional domain such that a chimeric polypeptide is encoded in a cell and/or in a subject.
• “Expression” is construed as to include any step involved in the production of the peptide or polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification and secretion.
• control sequence is defined herein to include all components which are necessary or advantageous for the expression of a polypeptide.
• control sequences include a promoter and transcriptional and translational stop signals.
• a promoter represented by a nucleotide sequence present in a nucleic acid construct is operably linked to another nucleotide sequence encoding a peptide or polypeptide as identified herein.
• transformation refers to a permanent or transient genetic change induced in a cell following the incorporation of new DNA (i.e. DNA exogenous to the cell).
• new DNA i.e. DNA exogenous to the cell.
• the term usually refers to an extrachromosomal, self- replicating vector which harbors a selectable antibiotic resistance.
• an "expression vector” may be any vector which can be conveniently subjected to recombinant DNA procedures and can bring about the expression of a nucleotide sequence encoding a polypeptide of the invention in a cell and/or in a subject.
• promoter refers to a nucleic acid fragment that functions to control the transcription of one or more genes or nucleic acids, located upstream with respect to the direction of transcription of the transcription initiation site of the gene.
• a promoter preferably ends at nucleotide -1 of the transcription start site (TSS).
• polypeptide refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein.
• a polypeptide is comprised of consecutive amino acids.
• the term “polypeptide” encompasses naturally occurring or synthetic molecules.
• sequence information as provided herein should not be so narrowly construed as to require inclusion of erroneously identified bases.
• the skilled person is capable of identifying such erroneously identified bases and knows how to correct for such errors.
• the verb "to comprise” and its conjugations is used in its non- limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
• the verb "to consist” may be replaced by "to consist essentially of meaning that a product or a composition or a nucleic acid molecule or a peptide or polypeptide of a nucleic acid construct or vector or cell as defined herein may comprise additional component(s) than the ones specifically identified; said additional component(s) not altering the unique characteristic of the invention.
• reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements.
• the indefinite article “a” or “an” thus usually means “at least one”.
• a subject suffering from cutaneous T-cell lymphoma is treated by topical administration of an endolysin according to the invention specific for Staphylococcus aureus.
• an endolysin according to the invention specific for Staphylococcus aureus.
• STAT3 activation and IL-10 and IL-17 expression are efficiently reduced, thereby treating the cancer.
• Example 2 Analysis of the effect of Staphylococcus aureus alpha-toxin on malignant T-cells and non-malignant T-cells such as cytotoxic T-cells. Summary
• Staphylococcus aureus alpha-toxin inhibits the proliferation of non-malignant T-cells, such as cytotoxic T-cells, but not of malignant T-cells.
• Staphylococcus aureus alpha-toxin inhibits cytotoxic activity of CTCL-specific cytotoxic CD8 T-cells. This implicates that the killing of cancer cells by cytotoxic T- cells is inhibited by Staphylococcus aureus alpha-toxin resulting in escape of tumour cells from killing and that Staphylococcus aureus alpha-toxin favours growth and survival of tumour cells. It follows that treatment targeting the alpha-toxin producing Staphylococcus aureus of patients with T cell lymphoma effectively treats the CTCL.
• Staphylococcus aureus alpha-toxin in T-cell lymphoma, it was investigated what the influence of Staphylococcus aureus alpha-toxin on proliferation of non-malignant T-cells, such as cytotoxic T-cells, and of malignant T-cells is; specifically whether there is a difference in proliferation in the presence of Staphylococcus aureus alpha-toxin.
• Proliferation of patient-derived malignant and non-malignant CTCL cell lines was measured in the presence and absence of Staphylococcus aureus alpha-toxin by a standard 3 H-Thymidine incorporation assay.
• a CTL assay (LDH, lactate dehydrogenase) release assay was performed using MART-1 specific CD8 T-cells as effector cells and Mad cells pulsed with MART- 1 peptide (ELAGIGILTV: SEQ ID NO: 75:) as target cells, in the presence and absence of Staphylococcus aureus alpha-toxin.
• LDH lactate dehydrogenase
• Malignant T-cell line Myl_a2059 cells (Acc No: RRID:CVCL_5342 (Woetmann et al, 2007)) were plated on 96 well plates at a cell density of 1 ,250 cells per well, while non-malignant T-cell line Myl_a1850 cells (Acc No: RRID:CVCL_M415 (Woetmann et al, 2007)), were plated at a cell density of 2,500 cells per well.
• Cells were cultured at 37°C in 20 ⁇ medium RPMI-1640 at 5% C0 2 as described in Levring et al, 2015, while being exposed to 2-fold increasing concentrations of alpha- toxin (List lab, Cat. No. #120).
• Thymidine [Methyl- 3 H] (PerkinElmer, Cat. No. NET027250UC) was added for an additional 24 hrs. After harvesting the 96 well plate onto a filter plate using a FilterMateHarvester (PerkinElmer), the filter plate was dried overnight; subsequently 20 ⁇ MicroScintTM-20 cocktail (PerkinElmer, Cat No. 6013621 ) to each well on the counting filter. The filter was then analysed with a TopCount®NXTTM Microplate Scintillation and Luminescence Counter (Packard), counting the incorporated thymidine as counts per minutes (cpm), indirectly reflecting cell proliferation. Counts were normalized to the toxin untreated sample within each group.
• CD8 effector cells (Sorensen et al, 2009) were pre-treated with 1.5ig/m ⁇ alpha-toxin (Sigma, Cat. No. H9395-.5MG) for 2hrs at, while Mad target cells (Acc No: RRID:CVCL_H631 (Davis et al, 1992)) were pulsed with 1 ⁇ of MART- 1 peptide at 37°C.
• Cells were plated in phenol free X-VIVO (Lonza, Cat. No. BE02-061 Q) media with effector target ratios of 1 :4, 1 :2 and 1 : 1.
• Staphylococcus aureus alpha-toxin inhibits killing of cancer cells by CD8 cytotoxic T-cells.
• proliferation of malignant cells is not inhibited by Staphylococcus aureus alpha-toxin while proliferation of non- malignant T-cells is inhibited by Staphylococcus aureus alpha-toxin, providing a selective advantage to malignant T-cells, resulting in outgrowth of malignant cells at the expense of non- malignant cells.

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